Lysophosphatidic acid (1-acyl-2-hydroxy-sn-glycero-3-phosphate; LPA) is a bioactive lipid mediator derived from membrane lipids through the actions of several enzymatic reactions involving phospholipase A2 and lysophospholipase D, lysoPLD/autotaxin (Moolenaar, 2007; Nakanaga, 2010). LPA plays a role in several cellular functions such as proliferation, differentiation, survival, migration and invasion. These functions influence many physiological and pathological processes including angiogenesis, wound repair, fibrosis, inflammation and carcinogenesis. Small molecule compounds that antagonize LPA receptors can be used in the treatment of diseases, disorders or conditions that are dependent on or mediated by LPA (Tigyi, 2010).
LPA acts on G protein-coupled receptors (GPCRs) on target cells. LPA binding to specific GPCRs of 6 subtypes (LPA1, LPA2, LPA3, LPA4, LPA5, LPA6) activates intracellular signaling pathways to produce a series of biological responses (Chun, 2010). LPA1 (EDG2) is expressed in many tissues in adult humans (An, 1997). LPA2 (EDG-4) is expressed in the human testis, pancreas, prostate, thymus, spleen, and peripheral blood leukocytes and in various cancer cell lines (An, 1998). LPA3 (EDG-7) is expressed in human heart, pancreas, prostate, testis, lung, ovary, and brain (Bandoh, 1999). LPA4 (p2y9/GPR23), LPA5 (GPR92) and LPA6 (p2y5) are members of the purinoceptor cluster of GPCRs and are more remotely related to LPA1, LPA2 and LPA3 (Tigyi, 2010).
LPA has long been known as a mitogen for fibroblasts (van Corven, 1989) and as a factor that stimulates production of connective tissue growth factor (CTGF) which promotes fibrosis (Hahn, 2000; Jeon, 2008). LPA also induces expression and activation of a chloride channel that is required for fibroblast-to-myofibroblast differentiation during wound healing (Yin, 2008). More recent studies showed that LPA plays a role in kidney (Pradere, 2007), liver (Watanabe, 2007), eye (Yin, 2008) and lung fibrosis (Tager, 2008). In animal models, LPA1 gene deletion and pharmacological inhibition of the LPA1 receptor suppressed the progression of fibrosis (Pradere, 2007; Tager, 2008; Swaney, 2010). Thus, LPA1 receptor antagonist may become novel therapies for the treatment of fibrosis.
Also, LPA and its GPCRs may play a role in the development of several types of cancers (Mills and Moolenaar, 2007). LPA is a mitogen that increases proliferation of many cell types, including tumor cells (Yang, 2005). LPA may also contribute to tumor progression by increasing motility and invasiveness of cells. Autotaxin (ATX) is a pro-metastatic enzyme initially isolated from the conditioned medium of human melanoma cells that stimulates a number of biological activities, including angiogenesis and the promotion of cell growth, migration, survival, and differentiation through the production of LPA. LPA receptor antagonist Ki16425 blocked the LPA-induced and ascites-induced invasion activity of a highly peritoneal metastatic pancreatic cancer cell line (Yamada, 2004). Ki16425 also inhibited metastasis of breast cancer cells to bone in animal models (Boucharaba, 2006). Therefore, genetic or pharmacological inhibition of LPA receptor signaling represents new approaches for cancer therapies.
Otherwise, after LPA is released at the site of tissue injury, LPA1 plays an important role in the initiation of neuropathic pain (Inoue, 2004).